Impaired selenoprotein expression in brain triggers striatal neuronal loss leading to co-ordination defects in mice

Abstract

Selenocysteine Insertion Sequence (SECIS)-Binding Protein 2 (Secisbp2) binds to SECIS elements located in the 3′-untranslated region of eukaryotic selenoprotein mRNAs. It facilitates incorporation of the rare amino acid selenocysteine in response to UGA codons. Inactivation of Secisbp2 in hepatocytes greatly reduced selenoprotein levels. Neuron-specific inactivation of Secisbp2 (CamK-Cre; Secisbp2fl/fl) reduced cerebral expression of selenoproteins to a lesser extent than inactivation of tRNA[Ser]Sec. This allowed us to study the development of cortical parvalbumin-positive (PV+) interneurons, which are completely lost in tRNA[Ser]Sec mutants. PV+ interneuron density was reduced in the somatosensory cortex, hippocampus, and striatum. In situ-hybridization for Gad67 confirmed the reduction of GABAergic interneurons. Because of the obvious movement phenotype involving a broad, dystonic gait, we suspected basal ganglia dysfunction. Tyrosine hydroxylase expression was normal in substantia nigra neurons and their striatal terminals. However the densities of striatal PV+ and Gad67+ neurons were decreased by 65% and 49%, respectively. Likewise, the density of striatal cholinergic neurons was reduced by 68%. Our observations demonstrate that several classes of striatal interneurons depend on selenoprotein expression. These findings may offer an explanation for the movement phenotype of selenoprotein P-deficient mice and the movement disorder and mental retardation described in a patient carrying SECISBP2 mutations.

Update on Selenoprotein Biosynthesis

“…To further analyze SBP2 function in organs not accessible in patients, mice models have been developed. While gene inactivation leads to embryonic lethality (123), the conditional deletion of SBP2 is less detrimental than Sec-tRNA [Ser]Sec inactivation and provides a tool for further in vivo functional analysis (124).…”

Selenocysteine incorporation: A trump card in the game of mRNA decay

“…Although not directly comparable, it was previously shown that the reduction of SBP2 in cultured cells by shRNA treatment resulted in a very different pattern of mRNA changes (Squires et al 2007), suggesting that there may exist cell-type specific regulatory networks. Similarly, the brain-specific reduction of SBP2 in mice showed a unique pattern of selenoprotein mRNA concentrations, further implicating SBP2 in regulating mRNA abundance (Seeher et al 2014a). Overall, the striking finding from these studies is the number of selenoprotein mRNAs that are unaffected by the lack of translation.…”

Effect of Dietary Selenomethionine Supplementation on Growth Performance, Tissue Se Concentration, and Blood Glutathione Peroxidase Activity in Kid Boer Goats

“…Previous studies have shown that Se has an important biochemical function in erythrocyte glutathione peroxidase activity (GSH-Px) [1,2]. Se promotes proper gait [3], healthy pregnancies [4,5], and growth [6,7] in animals. Its deficiency can cause nutritional and metabolic diseases [8,9] and can affect the immune system [10,11].…”